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Genetic Adaptation and
Selenium Uptake in
Vertebrates
Gaurab K Sarangi,
Introductory article
Article Contents
• Introduction
• Conclusions
Online posting date: 15th May 2017
Department of Evolutionary Genetics, Max Planck Institute
for Evolutionary Anthropology, Leipzig, Germany
Louise White,
Department of Evolutionary Genetics, Max Planck Institute for Evo-
lutionary Anthropology, Leipzig, Germany
Sergi Castellano,
Department of Evolutionary Genetics, Max Planck Institute for
Evolutionary Anthropology, Leipzig, Germany
Nutrients such as iron, zinc, selenium and iodine
are needed only in trace amounts but are nevertheless essential to the vertebrate diet. Of these, selenium and iodine are unusual in that their dietary
intake depends on their varying content in the soils
and waters across the world. Selenium in particular is required due to its function in selenoproteins, which contain the amino acid selenocysteine
(the twenty-first amino acid) as one of their constituent residues. This amino acid is encoded by
a termination codon, and its incorporation into
selenoproteins is mediated by numerous regulatory proteins. Vertebrate genomes have signatures
compatible with adaptation to the different levels of selenium in the world. These signatures are
shared among the genes using and regulating selenium and point to past and recent changes to the
metabolism and homeostasis of selenium in vertebrate species. Dietary selenium has thus shaped the
evolution of vertebrates throughout their history.
Introduction
Macronutrients and micronutrients
Nutrients are chemical components in the diet of an organism
required by it to survive and grow. Broadly, those nutrients
required in large quantities are called macronutrients, whereas
those required in small quantities are called micronutrients. While
macronutrients provide the bulk of an organism’s energy needs
to function, micronutrients are used to build and repair tissues
eLS subject area: Evolution & Diversity of Life
How to cite:
Sarangi, Gaurab K; White, Louise; and Castellano, Sergi (May
2017) Genetic Adaptation and Selenium Uptake in Vertebrates.
In: eLS. John Wiley & Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0026518
and to regulate body processes by providing the necessary cofactors for metabolism to be carried out. Elements such as carbon,
hydrogen, nitrogen, oxygen, sulfur and phosphorus are considered macronutrients, while elements like iron, zinc, manganese,
fluorine, copper, molybdenum, chromium, selenium and iodine
(listed here in decreasing order of dietary need by humans) belong
to the category of micronutrients (Mertz, 1981). While these
micronutrients are needed only in trace amounts in vertebrates
(e.g. from a few micrograms to milligrams per day in humans),
they are essential to life since their deficiency can lead to disease and even death (Hogstrand, 2016; Shenkin, 2001; Rayman,
2012). See also: Genetics of Human Zinc Deficiencies; Trace
Element Deficiency
Selenium in the diet
Of the essential micronutrients, selenium is unusual in that it has a
very narrow margin between nutritionally optimal and potentially
toxic (Wilber, 1980), making its uneven environmental distribution a challenge to the needs of the vertebrate diet. Diet is the
most important source of selenium, and its intake depends on the
selenium content of the soil on which food is gathered, hunted
or grown (Johnson et al., 2010; Ogle et al., 1988). Soil selenium levels, in turn, depend largely on the underlying bedrock
from which they are formed, which has created a patchwork of
deficient, adequate and sometimes toxic areas across the world
varying a hundredfold in their selenium levels. Selenium deficient
areas of thousands of km2 exist in parts of Northern Europe, East
Asia, Oceania and North America, with the selenium content of
Africa, South America and most parts of Asia remaining largely
unexplored (Oldfield, 2002; Selinus and Alloway, 2005).
The varying levels of selenium in the soils entering the food
chains of different vertebrates (both wild and farm animals) have
been shown to cause diseases either from its deficiency or toxicity (Kim and Mahan, 2003; (Flueck, 2015; (Sager, 2006). In
humans, mild selenium deficiency can cause immune dysfunction, reduced fertility, cognitive decline and increased risk of
mortality (Rayman, 2012). In severely selenium-deficient parts
of China, a disease of the heart muscle (Keshan disease), which
has a high mortality rate in children, and a disabling disease of
the bone and cartilage (Kashin–Beck disease) were endemic prior
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1
Genetic Adaptation and Selenium Uptake in Vertebrates
to the start of selenium supplementation programmes (Xia et al.,
2005). Indeed, selenium has a wide variance in dietary availability
around the world, and up to 1 billion people worldwide may have
a diet deficient in selenium (Nazemi et al., 2012). Its distribution around the world is, however, highly localised. For example,
China has both some of the highest and lowest soil selenium levels in the world (Oldfield, 2002).
Levels of selenium in waters worldwide also vary a hundredfold (Selinus et al., 2005), but oceans, seas and other aquatic
environments are generally an environmental sink for land
selenium (Selinus et al., 2005) with inorganic forms of selenium
being rapidly and efficiently bioaccumulated in phytoplankton
(100–1 000 000-fold enrichment from the water concentration
(Stewart et al., 2010)) and converted into organic forms of selenium that can enter the animal diet (Ogle et al., 1988). Indeed,
selenium bioaccumulation through the aquatic food chain has
made fish foods a major source of selenium in the human diet.
Thus, vertebrate species from different land and aquatic environments have evolved under different levels of selenium in their
diets.
The genetic basis of selenium use
The element selenium (with symbol Se) was first discovered in
1817, and owing to its similarity to tellurium (named after Tellus,
the Roman god of the earth), it was named after the titanic goddess of the moon, Selena (Berzelius, 1818). The role of selenium
in biology was, however, neither discovered nor investigated
until much later. Once selenium started being heavily used in
various industries in the late nineteenth century, its toxic effect on
humans came to the foreground (Dudley, 1938). In the 1930s, a
systematic study of poisoning symptoms of farm animals showed
their feed and the soil in which it is grown to have toxic levels of
selenium (Painter, 1941). Yet, it wasn’t until 1957 that selenium
was seen as an element essential to life despite its toxicity when
ingested in large amounts (Schwarz and Foltz, 1957).
In 1974, selenocysteine (with symbol Sec) was discovered
as the selenium-containing amino acid (Rother, 2015) through
which selenium is incorporated into proteins (Stadtman, 1974).
These selenium-containing proteins, known as selenoproteins,
are essential to life (Kasaikina et al., 2012). However, neither the
mechanism of its production nor of its incorporation into selenoproteins was known until later. In 1983 (Hawkes and Tappel,
1983), it was shown that rat liver can accomplish the de novo synthesis of selenocysteine from selenite and that this amino acid can
be incorporated into glutathione peroxidase via a transfer ribonucleic acid (tRNA) (see Glossary) that brings selenocysteine for
protein synthesis (selenocysteyl-tRNA). Moreover, the study suggested that selenocysteine could be coded for by a codon (see
Glossary) with a dual role in the genetic code – which was validated in 1986 (Chambers et al., 1986) when for the first time
a selenoprotein messenger ribonucleic acid (mRNA) (see Glossary) was sequenced. In this study, it was discovered that the
amino acid selenocysteine in the active site was encoded by an
in-frame UGA codon – a finding the authors considered highly
intriguing – since UGA was originally thought to serve only as a
termination codon See also: Selenocysteine. They further made
a note that some factor other than the UGA codon itself must be
2
responsible for its different usage. This was demonstrated in 1993
with the discovery of the SElenoCysteine Insertion Sequence
(SECIS) element, an ribonucleic acid (RNA) structure of about
60 nucleotides (see Glossary) responsible for directing the translation of the UGA codon into selenocysteine (Berry et al., 1993).
Soon it became evident that an elaborate machinery of cofactors
was required for the recoding of the UGA codon to incorporate
selenocysteine, and by the end of the 1990s, most of these factors
were discovered. In 1999, computational methods were developed to identify selenoproteins independently by two separate
groups (Lescure et al., 1999; Kryukov et al., 1999). In both cases
the key idea was that a SECIS element is absolutely required to
translate selenoproteins. Thus, they designed algorithms to look
for SECIS elements in mRNA sequences. Following these newly
developed methods, the race to find novel selenoproteins in complete genomes continued at full throttle and in less than a decade,
all the 25 human selenoprotein known to us today were correctly
identified (Kryukov et al., 2003; Gromer et al., 2005).
Annotation of selenoprotein genes
While the approaches required to correctly identify selenoproteins have been known for many years, most genomic databases
still wrongly annotate selenium-containing genes. This is mainly
because most databases use the UGA codon, a termination codon,
to identify the end of the open reading frame (ORF) (see Glossary) of each gene and ignore the possibility of the codon being
in-frame and co-translationally incorporating selenocysteine. To
address this problem, dedicated databases to selenoprotein genes
now exist (Castellano et al., 2008; Bekaert et al., 2010; Romagné
et al., 2014) that annotate thousands of selenoprotein genes in
dozens of species. SelenoDB 2.0 (Romagné et al., 2014) in
particular includes multiple transcripts for human selenoprotein
genes and single-nucleotide polymorphism (SNP) (see Glossary)
for many human populations worldwide. With the availability
of these correctly annotated selenoprotein genes, a number of
genetic studies previously unfeasible have now been undertaken.
Selenocysteine and cysteine
Selenocysteine is a structural analogue of the cysteine amino acid
with the sulfur ion in cysteine replaced by that of selenium. Cysteine is encoded by the UGC and UGT codons, a mutation away
from the selenocysteine UGA codon. We define a protein to be
cysteine containing, if it is homologous to a selenoprotein and
has a cysteine residue in place of selenocysteine. In 1996 (Stadtman, 1996), it was shown that a direct substitution of selenocysteine to cysteine in a selenoprotein reduces the catalytic activity
of the enzyme to 5% or less of the selenocysteine-containing
enzyme. This lower activity of cysteine, compared with selenocysteine, had been considered the main reason for the evolution and existence of selenoproteins even though a selenoprotein requires elaborate and resource hungry machinery. However, in 2003 (Gromer et al., 2003), it was demonstrated that a
cysteine-containing enzyme can approach the catalytic efficiency
of the corresponding selenoenzyme. This was a surprising result
showing that a few compensatory mutations were sufficient to
yield high selenium-independent activity, and the authors suggested that selenocysteine might not be essential for a particular
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Genetic Adaptation and Selenium Uptake in Vertebrates
diversity of selenoprotein genes and their regulatory regions in a
worldwide sample of human populations (White et al., 2015).
enzyme reaction but rather expands the metabolic capacities in
terms of activity towards a wider variety of substrates and over a
broad range of pH.
It remained unclear whether the distinct role of selenocysteine
compared with cysteine in selenoproteins illustrated the distinct
contribution of selenium to protein function. In 2009, Castellano, Andrés, and others set out to address this question from
an evolutionary perspective by the simultaneous identification of
the patterns of divergence in almost half a billion years of vertebrate evolution and diversity within the human lineage for the
full complement of enzymatic selenocysteine residues in these
proteomes. Their results indicated strong evolutionary constraint
on selenocysteine and cysteine sites across selenoproteomes (set
of selenoproteins in a genome), consistent with a unique role
of selenocysteine in protein function, low exchangeability with
cysteine and an unknown degree of functional divergence with
cysteine-containing homologues. They concluded that the distinct biochemical properties of selenocysteine, rather than the
geographical distribution of selenium, global oxygen levels (due
to the sensitivity of selenocysteine to oxidation – but see (Snider
et al., 2013) for an alternative view) or selenocysteine metabolic
cost, appeared to play a major role in the preservation of vertebrate selenoproteomes. The need for selenium in protein function despite its scarcity raises the possibility that selenoprotein
genes and genes that regulate selenium – through regulatory or
amino acid changes (other than selenocysteine) – have adapted
to the wide variation of selenium levels across the world. In this
regard, the evolutionary patterns of genes that use or regulate selenium have recently been investigated at two different time scales,
namely, (1) a longer time scale focusing on the divergence of
selenoprotein genes and genes that regulate selenium in vertebrate species and (2) a shorter time scale focusing on the genetic
Selenoproteins in vertebrates
The first vertebrates appeared on Earth about 530 million years
ago, and since then vertebrate species have adapted to most
of the Earth’s vast range of environments. These environments
differ widely in the availability of selenium, and vertebrates
depend on it today to different extents. Vertebrate species have
evolved to have a varying number of selenoprotein genes, ranging from 24 in mouse to 38 in zebrafish, with the ancestor of
all vertebrates carrying 28 selenoproteins (Mariotti et al., 2012).
Thus, despite the overall low exchangeability of selenocysteine
and cysteine residues (Castellano et al., 2009), vertebrates
have lost selenocysteine and gained cysteine in proteins a few
times. In addition, fishes have had multiple selenoprotein gene
duplications (see Figure 1). Apart from the selenoproteome
size, the number of selenocysteine residues in selenoprotein P
(SelP), which transports selenium from the liver to all other
tissues, varies in a wide range among different species (from 7
in guinea pigs to 18 in frogs) (see Figure 2). Since fishes have
a larger selenoproteome as well as more selenocysteine residues
transported by SelP than mammals, it has been suggested that
fishes have developed greater dependence on environmental
selenium, whereas mammals have reduced their reliance on it
(Lobanov et al., 2008). This would be in agreement with the sea
and other aquatic environments being an environmental sink for
land selenium (Selinus et al., 2005).
While this hypothesis needs to be tested, a more general question worth asking is whether the different availability of selenium
+
+
×
×
+
×
Placental Mammals (24–25)
Marsupial Mammals (25)
Birds and reptiles (25)
Amphibians (24)
28 Ancestral
selenoproteins
+
Ray-finned Fishes (35–38)
Cartilaginous Fishes (28)
Figure 1 Cartoon view of the loss (by gene deletion, in grey; by selenocysteine to cysteine mutation, in green) and gain (by gene duplication; in red) of
selenoprotein genes throughout vertebrate history. The range in the number of selenoprotein genes today is given in parenthesis for each vertebrate clade.
Based on Castellano, Andrés, et al. (2009); Mariotti et al. (2012).
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Genetic Adaptation and Selenium Uptake in Vertebrates
in various Earth environments constitutes an important selective pressure on the use and regulation of selenium throughout
vertebrate evolution. In an attempt to answer this question, compared the evolutionary forces acting on selenoproteins and genes
involved in the regulation of selenium and selenocysteine to those
acting on the cysteine-containing paralogous genes along the
vertebrate phylogeny. The evolutionary forces on proteins were
compared using the dN/dS ratio (see Glossary). If differences in
dietary selenium pose different selective pressures among vertebrate lineages, the selenium-related genes are expected to have
evolved under varying strengths of natural selection in vertebrates. At the same time, genes that do not depend on selenium
(cysteine-containing genes) are expected to be uninfluenced by
its abundance throughout the world and, hence, to evolve under
a more or less uniform strength of selection across vertebrate
species. They found that the strength of natural selection has
substantially changed across all vertebrates for genes that use
or regulate selenium and selenocysteine, while it does not vary
in the cysteine-containing genes. This suggests that selenium
availability, which differs widely among Earth environments,
has indeed played a role in shaping the evolution of multiple
vertebrate genes – suggesting polygenic adaptation – in multiple vertebrate lineages. They further compared the variation in
the strength of natural selection among the different vertebrate
clades. The results indicated that for the corresponding genes
that use (selenoproteins) or regulate selenium and selenocysteine
across vertebrates, the strength of selection varied most within
the fish clade.
More selenoproteins in fishes
In addition, fishes have the greatest number of selenoprotein
genes. While some of these additional genes in fishes were due to
the loss of the corresponding genes in other vertebrates, several
of them resulted from gene duplication (see Figure 1). Some of
these duplicated genes are found only in specific fish lineages and
were most likely the result of duplication events long after fishes
separated from other vertebrate species and each other. However,
seven genes trace back their origin to the ancestral fish lineage
and were most likely the result of an ancient whole genome
duplication event. Such an unusually high retention of duplicated
genes (7 of 28 genes present in the ancestral vertebrate) suggests
that fishes might have found new ways to use selenium in protein function. Indeed, the rate of evolution between gene copies
is quite uneven. That one copy of the duplicated gene accumulated amino acid changes faster than the other is suggestive of
neo-functionalization. This again would be in agreement with
the world waters being an environmental sink for land selenium
(Selinus et al., 2005). Thus, fishes may have generally evolved
with variable but ample selenium. Bioaccumulation through the
aquatic food chain may have contributed to this (Stewart et al.,
2010).
Selenium transport in fishes and other
vertebrates
Other than the largest selenoproteome size, fishes also have the
largest number of selenium atoms (in the form of selenocysteine)
transported in the plasma via SelP (except for frogs) (Lobanov
et al., 2008). Interestingly, the ability to transport selenium in
this protein is under strong evolutionary constraint in fishes,
whereas it has evolved neutrally in mammals and other non-fish
lineages. As a result, mammals and many other non-fish lineages
transport today about half of the selenium atoms that fishes do
in SelP (see Figure 2). This may be related to the size of their
selenoproteomes (Lobanov et al., 2008).
Primates (9–13)
Rodents (10,11)
Laurasiatheria (12–15)
Marsupials (14)
Reptiles (15)
Birds (13)
17 Ancestral
selenium atoms
in the form of
selenocysteine in
selenoprotein P
+
Amphibians (16–18)
Fishes (15–17)
Figure 2 Cartoon view of the loss (by selenocysteine to cysteine mutation, in green) and gain (by cysteine to selenocysteine mutation; in red) of selenium
atoms in selenoprotein P (SelP) throughout vertebrate history. The number of selenium atoms transported today by SelP is given in parenthesis for each
vertebrate clade. Some laurasiatheria are whales, dolphins, pigs, horses, cows, bats, cats, bears, hedgehogs and related species.
4
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Genetic Adaptation and Selenium Uptake in Vertebrates
Genetic variation in
human populations
Sub-Saharan African region
Middle Eastern region
European region
Central South Asian region
East Asian region
Oceania region
American region
Figure 3 Worldwide map of the human populations surveyed in White et al. (2015) to assess the patterns of polymorphism in 25 selenoprotein genes, 6
cysteine-containing genes and 19 genes that are involved in the metabolism and homeostasis of selenium.
Selenoproteins in humans
As humans migrated out of Africa around 60 000 years ago
(Fu et al., 2013), they came to live in a wide range of different
environments. In order to thrive in these diverse environments,
human populations have not only employed cultural and technological advances but have often also experienced adaptation
at the genetic level. One important factor to which humans have
adapted is variation in the composition of the diet in different
parts of the world. Such recent genetic adaptations in human
populations in response to variation in the human diet have
been demonstrated in recent scientific literature. Adaptation to
prolong the expression of lactase into adulthood has occurred
independently in African and European dairy-herding populations (Tishkoff et al., 2007; Olds and Sibley, 2003; Itan et al.,
2009). Similarly, it has been suggested that some populations
have locally adapted in response to the levels of iodine in their
environment (López Herráez et al., 2009).
Because adequate selenium intake is so important to human
health and fertility, and the levels of selenium in the diet vary
widely around the world, it could be hypothesised that differences in dietary selenium intake sustained over many generations
may have shaped the evolution of selenium-associated genes
in humans. To understand the evolution of the use of this
micronutrient in humans, White and colleagues (2015) surveyed
the patterns of polymorphism in all 25 selenoprotein genes, 6
cysteine-containing genes and 19 genes that are involved in their
regulation in 855 unrelated individuals from 50 human populations from around the world (see Figure 3). First, they looked
for local adaptation in selenium-related genes by measuring
population differentiation with the FST statistic (see Glossary)
according to the formula of Weir and Cockerham (1984) to see
if any parts of the world stand out from the others in terms of
unusually large differences in the frequency of genetic variants among populations. They found that selenoproteins and
regulatory genes show a signal of local adaptation in central
South Asia and East Asia. Most of the populations from East
Asia come from China, a part of the world known to have large
selenium-deficient regions (Oldfield, 2002; Xia et al., 2005).
Low-selenium soil has also been reported in Pakistan where
most of the central South Asian populations were sampled
(Cavalli-Sforza, 2005; Khan et al., 2006, 2008; Ahmad et al.,
2009). It therefore seems likely that these signals of positive
selection reflect adaptation to selenium levels in the environment.
In contrast, with cysteine-containing genes, they did not find any
signal of local adaptation in any part of the world, suggesting
that these genes are independent of selenium and in humans do
not have compensatory role in low selenium conditions. They
(White et al., 2015) further looked more closely at the signal
of adaptation in China, since it has been known to have large
selenium-deficient regions. They grouped the populations from
China by whether they live in regions that are selenium-deficient
or in selenium-adequate regions. The selenium-deficient regions
include areas where severe selenium deficiency diseases, such as
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5
Genetic Adaptation and Selenium Uptake in Vertebrates
Oroqen
Mongola
Xibo
Four least differentiated
populations
Tujia
She
Naxi
Miazou
Four most differentiated
populations
Low selenium levels
Dai
Adequate selenium levels
High selenium levels
Figure 4 Populations from China grouped by whether they live in regions that are selenium deficient or adequate. The selenium-deficient regions include
areas where severe selenium deficiency diseases, such as Keshan disease and Kashin–Beck disease, were endemic in the past. Populations living in the
selenium-deficient regions have allele frequency changes that differentiate them most from other populations.
Keshan disease and Kashin–Beck disease, were endemic in the
past (before selenium supplementation). This grouping revealed
that the signal of local adaptation within China is restricted to the
selenium-deficient regions of the country (see Figure 4). This
supports the idea that it is selenium deficiency that is driving
the adaptive signal. Interestingly, this adaptation results from the
concerted evolution of multiple genes – suggesting polygenic
adaptation – underlying the use and regulation of selenium and
not of individual genes. The results suggest that the micronutrient
selenium appears to have been important during recent human
evolution and, as humans spread around the world, adaptation
in the genes that incorporate selenium or regulate its use may
have helped humans to inhabit environments that are deficient
in selenium. This may result in human populations today having
different risks of selenium-related diseases.
around the world. It is then not surprising that recent evolutionary
studies suggest that vertebrates adapted to selenium availability
in ways other than abandoning its use. The strength of selection
on genes that use or regulate selenium has changed substantially
across vertebrates, whereas it has not in genes that have lost their
dependence on selenium. This suggests that selenium deficiency,
abundance and toxicity across the world have shaped vertebrate
evolution. In particular, fishes have genetic signatures of adaptations to abundant selenium, whereas humans (and possibly other
mammals) have genetic signatures compatible with adaptation to
selenium deficiency. In both cases, the adaptive signatures are
shared among genes that use or regulate selenium, suggesting
that it is the overall use, metabolism and homeostasis of selenium
that adapts to its long-term variation. A better understanding of
the mechanisms and the alleles underlying the local adaption of
humans and other vertebrates to selenium is needed.
Conclusions
Since the first discovery of selenocysteine and selenoproteins
in the 1970s, our understanding of them has come a long way.
Many novel selenoproteins have been identified and annotated.
However, not a lot has been known about the underlying forces
that shaped the evolution of the use of selenium in the proteins
of various lineages. While there have been a few hypothesis
regarding how the environment could have affected the evolution of selenium use in proteins, evolutionary tests on selenoprotein sequences are needed to confirm (or reject) them. In this
regard, evolutionary approaches have shown that selenocysteine
and cysteine are generally not exchangeable in vertebrate proteins
(Castellano et al., 2009), attesting to the unique role of selenium
in protein function. Thus, selenium in vertebrates is functionally indispensable despite its unevenness (from deficient to toxic)
6
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Stephan W (2016) Signatures of positive selection: from selective
sweeps at individual loci to subtle allele frequency changes in
polygenic adaptation. Molecular Ecology 25: 79–88.
eLS © 2017, John Wiley & Sons, Ltd. www.els.net